The histamine H3 receptor was first described as a presynaptic autoreceptor in the central nervous system (CNS) (Arrang, J.-M. et al. Nature 1983, 302, 832-837) controlling the synthesis and release of histamine. The histamine H3 receptor is primarily expressed in the mammalian central nervous system (CNS), with some minimal expression in peripheral tissues such as vascular smooth muscle.
Thus, several indications for histamine H3 antagonists and inverse agonists have been proposed based on animal pharmacology and other experiments with known histamine H3 antagonists (e.g. thioperamide). (See: Krause et al. and Phillips et al. in “The Histamine H3 Receptor-A Target for New Drugs”, Leurs, R. and Timmerman, H., (Eds.), Elsevier, 1998, pp. 175-196 and 197-222; Morisset, S. et al. Nature 2000, 408, 860-864.) These include conditions such as cognitive disorders, sleep disorders, psychiatric disorders, and other disorders.
For example, histamine H3 antagonists have been shown to have pharmacological activity relevant to several key symptoms of depression, including sleep disorders (e.g. sleep disturbances, fatigue, and lethargy) and cognitive difficulties (e.g. memory and concentration impairment), as described above. For reviews, see: Bonaventure, P. et al. Biochem. Pharm. 2007, 73, 1084-1096; Letavic, M. A. et al. Prog. Med. Chem. 1996, 44, 181-206. There remains a need for potent histamine H3 receptor modulators with desirable pharmaceutical properties.
N-Benzoyl and N-benzylpyrrolidin-3-ylamines were disclosed as histamine H3 antagonists by Cole and co-workers (U.S. Pat. Appl. Publ. US 2007/0270440, Nov. 22, 2007). Certain amidine compounds were described as serine protease inhibitors in U.S. Pat. Appl. Publ. US 2002/0055469 (May 9, 2002). Certain prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were described as VLA-4 antagonists for inflammatory conditions (Chiba et al. Bioorg. Med. Chem. 2006, 14, 2725-2746). Aminomethylazetidines were prepared by Boros et al. (J. Het. Chem. 2006, 43(2), 371-388). Proline derivatives were shown as DPP-IV modulators in U.S. Pat. Appl. Publ. US 2004/0106655 (Jun. 3, 2004).